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Role of HslVU across different eukaryotic phyla

This interesting contribution by Li et al describes homologs of the bacterial proteasome component HslVU in Trypanosoma brucei. The authors show that the TbHslVU complex localizes inside the mitochondrion, and knockdown by RNAi results in defective kDNA segregation, specifically of the minicircles. While relegated to more humble clean up in the aftermath of heat shock in bacteria the authors suggest that HslVU in the trypanosome mitochondrion acts akin to its eukaryotic counterpart as a major regulator of cell cycle progression. The hypothesis put forward in the discussion is that HslVU-mediated degradation of one (or more) of the proteins that associate with the minicircle origin of replication such as UMSBP or p38 prevents undue over-replication. At this point there is no experimental evidence for a link between HslVU and the stability and regulation of these proteins. However, the introduction of tagged versions of these genes (e.g. the GFP tagged p38 described by Liu and colleagues (1)) into the HslVU RNAi strains should make this readily testable. The expectation would be that these proteins accumulate in TbHslVU RNAi cells.

The authors speculate that the trypanosomatids may have adopted the use of the endosymbiotic HslVU to assist in the complex task of kDNA network segregation. However, as the authors also mention, HslVU also seems to be present in other non-kinetoplastid protozoa such as apicomplexan parasites as well as some Amoebozoa, Chromalveolata, Rhizaria, and Excavata species (2). Looking a little closer at the Apicomplexa we note that while the gene for HslVU is present in Toxoplasma gondii and Plasmodium falciparum, it is absent in Cryptosporidium parvum, which harbors a highly reduced mitochondrion. Furthermore, our (admittedly quick) BLAST searches failed to reveal HslVU homologs in Giardia intestinalis, Entamoeba histolytica, or Trichomonas vaginalis. Interestingly while some of these species harbor residual mitochondria often dubbed mitosomes they all lack mitochondrial genomes. This may suggest that rather than a highly specialized role in kDNA network segregation specifically, HslVU may serve important roles in mitochondrial genome biology across several different eukaryotic phyla. Based on sequence data and predictions alone, it is unclear whether the T. gondii and P. falciparum homologs are targeted to the mitochondrion. Localization studies and characterization of the HslVU homologs in these organisms might help to determine more definitively why the HslVU complex was retained in these eukaryotes.

RE: Role of HslVU across different eukaryotic phyla

The points raised by Relff and Striepen are well taken. Identification of the substrates of TbHslVU is indeed the very crucial next step in this study and UMSBP and p38 are definitely among the most likely candidates at this time.

Relff and Striepen also advanced the interesting idea that HslVU could play important functions in regulating mitochondrial DNA replication among parasitic protozoa since its homologs are found in mitochondria-containing P. falciparum and T. gondii but not among the amitochondrial organisms such as E. histolytica, G. lamblia and T. vaginalis. A very provocative thinking! My only concern for the moment is that the HslVU homologs in P. falciparum do not possess apparent mitochondrial targeting signals, whereas those in T. gondii do have the signals albeit with varying scores. I agree with Reiff and Striepen that the most important study will be to localize these homologs first if they are at all expressed in these parasites. A mitochondrial localization would initiate a series of significant studies, whereas a cytoplasmic location would cast some doubts on their biological significance since regular eukaryotic proteasomes are known to exist in these protozoan parasites.